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Supplementary Table S2 shows the effect of aspirin on MDA-MB-231 lung metastasis in vivo

supplementary Figure S1 shows the annotated spectrum of VFQVVESTRPGK (326-337) from heparanase

Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of small-molecule inhibitors of heparanase. Clin Cancer Res; 23(20); 6267–78. ©2017 AACR.

Microalgae cannot meet the bait demand for aquaculture due to light intensity limitation and other disadvantageous conditions. This research selected 6 mixotrophic microalgae, and the optimal strains and organic carbon were screened. The results showed that Thalassiosira pseudonana and Chlorella sp. are suitable for mixotrophic culture. The maximum cell density of Thalassiosira pseudonana was found to be 1.67 times than that of the photoautotrophic group when glycerol was added. The maximum cell density of Chlorella sp. with acetic acid was 1.69 times than that of the photoautotrophic group. When the concentration of acetic acid was 5.0 g·L

The accurate estimation of the optical properties of turbid media by using a spatially resolved (SR) technique remains a challenging task due to measurement errors in the acquired spatially resolved diffuse reflectance (SRDR) and challenges in inversion model implementation. In this study, what we believe to be a novel data-driven model based on a long short-term memory network and attention mechanism (LSTM-attention network) combined with SRDR is proposed for the accurate estimation of the optical properties of turbid media. The proposed LSTM-attention network divides the SRDR profile into multiple consecutive and partially overlaps sub-intervals by using the sliding window technique, and uses the divided sub-intervals as the input of the LSTM modules. It then introduces an attention mechanism to evaluate the output of each module automatically and form a score coefficient, finally obtaining an accurate estimation of the optical properties. The proposed LSTM-attention network is trained with Monte Carlo (MC) simulation data to overcome the difficulty in preparing training (reference) samples with known optical properties. Experimental results of the MC simulation data showed that the mean relative error (MRE) with 5.59% for the absorption coefficient [with the mean absolute error (MAE) of 0.04 cm-1, coefficient of determination (R2) of 0.9982, and root mean square error (RMSE) of 0.058 cm-1] and 1.18% for the reduced scattering coefficient (with an MAE of 0.208 cm-1, R2 of 0.9996, and RMSE of 0.237 cm-1), which were significantly better than those of the three comparative models. The SRDR profiles of 36 liquid phantoms, collected using a hyperspectral imaging system that covered a wavelength range of 530-900 nm, were used to test the performance of the proposed model further. The results showed that the LSTM-attention model achieved the best performance (with the MRE of 14.89%, MAE of 0.022 cm-1, R2 of 0.9603, and RMSE of 0.026 cm-1 for the absorption coefficient; and the MRE of 9.76%, MAE of 0.732 cm-1, R2 of 0.9701, and RMSE of 1.470 cm-1for the reduced scattering coefficient). Therefore, SRDR combined with the LSTM-attention model provides an effective method for improving the estimation accuracy of the optical properties of turbid media.

Binary titanium–niobium (Ti–Nb) alloys have recently been attracted due to low Young’s moduli and non-toxic properties. This study explores the influence of low Nb content (0–25 wt%) on the comprehensive parameters of tensile stress–strain relationships (ultimate strength (σUTS), yield strength (σ0.2) and elastic modulus (E)), surfaces properties (Vickers microhardness, surface roughness (Ra), water contact angle (WCA), X-ray diffraction (XRD) and scanning electron microscopy (SEM)), corrosion resistance (in artificial saliva and lactic acid) and biological properties (cytotoxicity and alkaline phosphatase activity of MC3T3-E1 pre-osteoblasts) of Ti–xNb alloys (x = 5, 10, 15, 20 and 25 wt%), with using commercially pure grade 2 titanium (cp-Ti) as control. XRD results shown that all the Ti–xNb alloys comprised α + β Ti alloy phases, such that the β phase increased correspondingly with the increased amount of Nb in the alloy, as well as the reduction of E (69–87 GPa). Except Ti–5Nb, all other Ti–xNb alloys showed a significantly higher hardness, increased σUTS and σ0.2, and decreased WCA compared with cp-Ti. No corrosion was detected on Ti–xNb alloys and cp-Ti in artificial saliva and lactic acid solutions. The cytotoxicity of Ti–xNb alloys was comparable to that of cp-Ti in MC3T3-E1 pre-osteoblasts without interference from differentiation behaviour, but the proliferation rate of the Ti–5Nb alloy was lower than other groups. In overall, binary Ti–(10–25 wt%)Nb alloys are promising candidate for orthopaedic and dental implants due to their improved mechanical properties and comparable biological performance, while Ti–5Nb should be used with caution.

Background Chronic kidney disease (CKD) leads to end-stage renal failure and cardiovascular events. An attribute to these progressions is abnormalities in inflammation, which can be evaluated using the neutrophil-to-lymphocyte ratio (NLR). We aimed to investigate the association of NLR with the progression of end stage of renal disease (ESRD), cardiovascular disease (CVD) and all-cause mortality in Chinese patients with stages 1–4 CKD. Methods Patients with stages 1–4 CKD (18–74 years of age) were recruited at 39 centers in 28 cities across 22 provinces in China since 2011. A total of 938 patients with complete NLR and other relevant clinical variables were included in the current analysis. Cox regression analysis was used to estimate the association between NLR and the outcomes including ESRD, CVD events or all-cause mortality. Results Baseline NLR was related to age, hypertension, serum triglycerides, total serum cholesterol, CVD history, urine albumin to creatinine ratio (ACR), chronic kidney disease-mineral and bone disorder (CKD-MBD), hyperlipidemia rate, diabetes, and estimated glomerular filtration rate (eGFR). The study duration was 4.55 years (IQR 3.52–5.28). Cox regression analysis revealed an association of NLR and the risk of ESRD only in patients with stage 4 CKD. We did not observe any significant associations between abnormal NLR and the risk of either CVD or all-cause mortality in CKD patients in general and CKD patients grouped according to the disease stages in particular. Conclusion Our results suggest that NLR is associated with the risk of ESRD in Chinese patients with stage 4 CKD. NLR can be used in risk assessment for ESRD among patients with advanced CKD; this application is appealing considering NLR being a routine test. Trial registration ClinicalTrials.gov Identifier NCT03041987. Registered January 1, 2012. (retrospectively registered) (https://www.clinicaltrials.gov/ct2/show/NCT03041987?term=Chinese+Cohort+Study+of+Chronic+Kidney+Disease+%28C-STRIDE%29&rank=1)

A thermo-electric coupled model of sinusoidal alternating current (AC) heating for lithium-ion power batteries is proposed in this paper. The model combines the equivalent circuit model with the heat generation model in frequency domain. The model is validated against the experimental results of sinusoidal AC heating with different amplitudes and frequencies of current. An optimal strategy of sinusoidal AC heating based on battery safe operating voltage limit is proposed . It is found that in the high frequency region, the maximum current amplitude under the safety voltage limit is larger, the maximum heat generation rate of the battery is larger, and the battery can be heated from -20°C to 0°C within 480s.

Aggregated metastatic cancer cells, referred to as circulating tumor cell (CTC) clusters, are present in the blood of cancer patients and contribute to cancer metastasis. However, the origin of CTC clusters, especially intravascular aggregates, remains unknown. Here, we employ suspension culture methods to mimic CTC cluster formation in the circulation of breast cancer patients. CTC clusters generated using these methods exhibited an increased metastatic potential that was defined by the overexpression of heparanase (HPSE). Heparanase induced FAK- and ICAM-1-dependent cell adhesion, which promoted intravascular cell aggregation. Moreover, knockdown of heparanase or inhibition of its activity with JG6, a heparanase inhibitor, was sufficient to block the formation of cell clusters and suppress breast cancer metastasis. Our data reveal that heparanase-mediated cell adhesion is critical for metastasis mediated by intravascular CTC clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression.

// Chao Wang 1, * , Xiangying Kong 1, * , Chunyan Zhu 1 , Chunfang Liu 1 , Danni Sun 1 , Qionghong Xu 1 , Zhiyun Mao 1 , Qingxia Qin 1 , Hongchang Su 1 , Danqiao Wang 2 , Xiaoliang Zhao 2 and Na Lin 1 1 Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China 2 Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China * These authors have contributed equally to this work Correspondence to: Na Lin, email: linna888@163.com Keywords: Wu-tou decoction (WTD), neuropathic pain (NP), glia-mediated neuroinflammation, astrocytic IL-1R1/TRAF6/JNK signaling, anti-hyperalgesia Received: June 14, 2017 Accepted: August 26, 2017 Published: October 06, 2017 ABSTRACT Neuropathic pain (NP) caused by nerve injuries continues to be an intractable challenge due to inadequate therapeutic strategies. Recent study demonstrated glia-induced neuro-inflammation in the spinal cord, especially the activation of astrocytes, plays an essential role in the development of NP, which opens new avenues for NP treatment. In this study, we explored the anti-hyperalgesia properties of Wu-tou decoction (WTD) and showed that WTD potently attenuates mechanical allodynia and heat hyperalgesia in lumbar 5 (L5) spinal nerve ligation (SNL)-induced NP without noticeable side effect or affecting basal pain perception of mice. Mechanistically, initial targets screening tests indicated WTD's analgesic action may be centrally mediated within the spinal cord, which further verified by its inhibitory actions on glia-releasing factors of IL-1β, CCL2 and CXCL1. Meanwhile, WTD significantly reduced spinal IL-1R1, TRAF6 expressions, p-JNK levels, and number of GFAP/IL-1R1, GFAP/TRAF6, GFAP/p-JNK positive astrocytes in the superficial lamina of spinal cord. Additionally, co-administration of IL-1Ra increased the anti-hyperalgesia effects of WTD and further decreased CCL2 and CXCL1 expressions, while no synergistic effects were detected when TRAF6 or JNK inhibitors were co-administrated with WTD. Thus, our data suggested that the effective inhibition of spinal astrocytic IL-1R1/TRAF6/JNK signaling (especially IL-1R1) contributes, at least in part, to WTD's anti-hyperalgesia action. It also indicates that WTD might be a promising candidate for the treatments of chronic pain, especially under NP-related neurological disorders.

Aspirin is associated with a reduced risk of cancer and delayed progression of malignant disease. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mTOR signaling is believed to partially contribute to these anticancer effects, although the mechanism is unclear. In this study, we revealed the mechanism underlying the effects of aspirin on AMPK-mTOR signaling, and described a mechanism-based rationale for the use of aspirin in cancer therapy. We found that aspirin inhibited mTORC1 signaling through AMPK-dependent and -independent manners. Aspirin inhibited the AMPK-TSC pathway, thus resulting in the suppression of mTORC1 activity. In parallel, it directly disrupted the mTOR-raptor interaction. Additionally, the combination of aspirin and sorafenib showed synergetic effects via inhibiting mTORC1 signaling and the PI3K/AKT, MAPK/ERK pathways. Aspirin and sorafenib showed synergetic anticancer efficacy in the SMMC-7721 model. Our study provides mechanistic insights and a mechanism-based rationale for the roles of aspirin in cancer treatment.

Wu-tou Decoction (WTD) is a classic herbal formula in traditional Chinese medicine for the treatment of joint diseases, neuropathic pain (NP) and inflammatory pain. In this study we investigated whether WTD produced analgesic action in a mouse spinal nerve ligation (SNL) model and elucidated the underlying molecular mechanisms. Mice were subjected to SNL and orally treated with WTD (3.15, 6.30 or 12.60 g·kg(−1)·d(−1)) for 21 d. SNL induced mechanical hyperalgesia and heat hyperalgesia characterized by rapid and persistent pain hypersensitivity. In addition, the expression levels of IL-1β, TNF-α, CCL2 and CXCL1 in the spinal cord dorsal horn were dramatically increased on the 10(th) d post-surgery. Oral administration of WTD dose-dependently suppressed both mechanical and heat hyperalgesia as well as the expression levels of inflammatory cytokines in the spinal cord dorsal horn on the 21(st) d post-surgery. Then whole-genome microarray analyses were conducted to detect the gene expression profiles of spinal cord dorsal horn in SNL mice with or without WTD treatment. After construction of the WTD-SNL-network and topological analysis, a list of candidate target genes of WTD acting on SNL-induced NP was identified and found to be functionally enriched in several glial cell activation-related pathways and neuroinflammatory pathways. Our data have clarified the gene expression patterns in the mouse spinal cord under the NP condition. We also demonstrate the analgesic action of WTD through suppression of glial cell activation and neuroinflammation, which suggest the potential of WTD as a promising candidate for the treatment of NP.

The resourceful combination of distinct Mg, Zn and Si active-sites within a single aluminophosphate framework, via simultaneous isomorphous substitution, has afforded unique bimetallic nanoporous heterogeneous catalysts. Unique site-specific interactions have been engineered, at the molecular level, to facilitate catalytic modifications and optimize product yield. By the dextrous incorporation of individual transition-metal active centres, we are able to intricately control the precise nature of the Brønsted acid sites, thereby influencing their catalytic behaviour for the industrially relevant acid-catalysed Beckmann rearrangement of cyclohexanone oxime and isopropylation of benzene.

Wu-tou decoction (WTD) is a classic traditional Chinese medicine formula and has been extensively used for the treatment of rheumatoid arthritis (RA). Previous reports indicate that WTD possesses anti-inflammatory and antinociceptive activities, and inhibits the development of arthritic joints and disease severity of collagen-induced arthritis (CIA) or adjuvant-induced rats; however, its action on angiogenesis of RA has not been clarified. This study aims to determine the anti-angiogenic activity of WTD in CIA rats and in various angiogenesis models. Our data showed that WTD (0.95, 1.9, and 3.8 g/kg) markedly reduced the immature blood vessels in synovial membrane tissues of inflamed joints from CIA rats. It also inhibited in vivo angiogenesis in chick embryo and VEGF

Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin. Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model. Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner. Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of small-molecule inhibitors of heparanase. Clin Cancer Res; 23(20); 6267–78. ©2017 AACR.

Cofilin, an actin-binding protein which disassembles actin filaments, plays an important role in invasion and metastasis. Here, we discover that JG6, an oligomannurarate sulfate, binds to cofilin, suppresses the migration of human breast cancer cells and cancer metastasis in breast cancer xenograft model. Mechanistically, JG6 occupies actin-binding sites of cofilin, thereby disrupting cofilin modulated actin turnover. Our results highlight the significance of cofilin in cancer and suggest JG6, a cofilin inhibitor, to treat metastatic cancer.

Overcharging is one of the main reasons causing lithium-ion battery thermal abuse, probably leading to vehicle accidents. This paper develops an impedance-based method to characterize the battery heat generation during overcharging process. An electro-thermal model is adopted for better computation efficiency. A series of overcharging experiments at 30 ℃ and 60 ℃ are conducted. Interestingly, three stages can be identified from the results, which are the normal heat-accumulating stage, fast heat-accumulating stage and thermal runaway stage, respectively (Stage I, II and III). During Stage I and II, pulse-relaxation and impedance-measurement methods are developed to parameterize the electro-thermal model, under different state of charge, temperature and charging rate conditions. Results of genetic algorithm with Hybrid Pulse Power Characteristic cycling data are used as benchmark. The simulated surface temperature results during overcharging are validated via experiments, which shows that medium frequency impedance method outputs better equivalent resistance and surface temperature estimation accuracy. The proposed model achieves to reduce the temperature estimation root mean squared error to under 0.9 ℃ in all overcharging situations, with greatly reduced computation complexity.

In order to solve the application bottleneck of electric vehicles in alpine-cold regions, sinusoidal alternating current heating becomes a competitive method. A novel thermo-electric coupled model for lithium-ion power batteries at low temperatures is proposed in this paper. The model combines the thermal model with the electrochemical impedance model. Model parameters are identified by genetic algorithm through programming in MATLAB. Plenty of experiments have validated the model and explored the influence factors of the heat generation effect. It is found that as the battery temperature increases, the optimal current amplitude increases gradually, whereas the optimal current frequency decreases. Therefore, an original temperature dependent control approach of sinusoidal alternating current heating is proposed and the strategy is optimized by sequential quadratic programming algorithm, considering safe operating voltage constraints. The optimal frequency range is distributed in the high frequency region, which makes the allowable safe current larger and thus gives a larger heat generation rate, and lithium ion deposition does not occur. Finally, the optimized heating strategy is verified by experiments. Results show that the battery module can achieve a temperature rise from −20 °C to 0 °C in 520 s, with an average temperature-rise 2.31 °C/min.

O-GlcNAcylation is a post-translational modification that regulates a broad range of nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes. Previous studies have shown that increased levels of global O-GlcNAcylation and O-GlcNAc transferase (OGT) are linked to the incidence of metastasis in breast cancer patients, but the molecular basis behind this is not fully known. In this study, we have determined that the actin-binding protein cofilin is O-GlcNAcylated by OGT and mainly, if not completely, mediates OGT modulation of cell mobility. O-GlcNAcylation at Ser-108 of cofilin is required for its proper localization in invadopodia at the leading edge of breast cancer cells during three-dimensional cell invasion. Loss of O-GlcNAcylation of cofilin leads to destabilization of invadopodia and impairs cell invasion, although the actin-severing activity or lamellipodial localization is not affected. Our study provides insights into the mechanism of post-translational modification in fine-tuning the regulation of cofilin activity and suggests its important implications in cancer metastasis.

Anemone flaccida Fr. Schmidt is used in the clinical compound prescription for the treatment of rheumatoid arthritis (RA) in China and has the traditional use of draining dampness, diminishing swelling, and relieving pain. Total saponins (TS) are the characteristic components and also the main active ingredients of A. flaccida. Previous reports indicated that TS possess anti-inflammatory and immunoregulatory properties; however, the effects of TS on bone destruction of RA have not been evaluated. In this study, our data first showed the therapeutic effects of TS on severity of arthritis and arthritis progression in collagen-induced arthritis (CIA) rats. Then, by microfocal computed tomography (CT) quantification, TS significantly increased bone mineral density, bone volume fraction, and trabecular thickness and decreased trabecular separation of inflamed joints both at peri-articular and extra-articular locations. TS also diminished the level of the bone resorption marker CTX-I and simultaneously increased the bone formation marker osteocalcin in sera of CIA rats. Interestingly, TS prevented bone destruction by reducing the number of osteoclasts in inflamed joints, reducing the expression of receptor activator of nuclear factor-κF (RANK) ligand (RANKL) and RANK, increasing the expression of osteoprotegerin (OPG), at both mRNA and protein levels, and decreasing the ratio of RANKL to OPG in inflamed joints and sera of CIA rats. This was further confirmed in the co-culture system of human fibroblast-like synovial and peripheral blood mononuclear cells. In addition, TS inhibited the levels of pro-inflammatory cytokines implicated in bone resorption, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), IL-6, IL-17, and IL-23 in sera and joints. These findings offer convincing evidence that TS attenuate RA partially by preventing both focal bone destruction and systemic bone loss. This anti-erosive effect results in part from inhibiting osteoclastogenesis by regulating the RANKL/RANK/OPG signaling pathway. The suppression of systemic and local pro-osteoclastogenic cytokines by TS was also highly effective.

Wu-tou decoction (WTD) is a classic traditional Chinese medicine formula and has been used effectively to treat joint diseases clinically. Previous reports indicated that WTD possesses anti-inflammatory activity; however, its actions on pain have not been clarified. Here, we investigated the antinociceptive activity of WTD in CFA-induced mice, and its possible mechanism of the action associated with transient receptor potential (TRP) ion channels was also explored. Our results showed that 1.58, 3.15, and 6.30 g/kg WTD significantly attenuated mechanical, cold, and heat hypersensitivities. Moreover, WTD effectively inhibited spontaneous nociceptive responses to intraplantar injections of capsaicin and cinnamaldehyde, respectively. WTD also effectively suppressed jumping and wet-dog-shake behaviors to intraperitoneal injection of icilin. Additionally, WTD significantly reduced protein expression of TRPV1 and TRPA1 in dorsal root ganglia and skins of injured paw. Collectively, our data demonstrate firstly that WTD exerts antinociceptive activity in inflammatory conditions by attenuating mechanical, cold, and heat hypersensitivities. This antinociceptive effect may result in part from inhibiting the activities of TRPV1, TRPA1, and TRPM8, and the suppression of TRPV1 and TRPA1 protein by WTD was also highly effective. These findings suggest that WTD might be an attractive and suitable therapeutic agent for the management of chronic inflammatory pain.

Background Steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) presents great challenges due to the various effects of steroids on multi-system pathways involved into osteoblast differentiation, osteoblast and osteoclast apoptosis, lipid metabolism, calcium metabolism and coagulation. As one of the most frequently used herbs in Traditional Chinese Medicine formulas that are prescribed for the regulation of bone and mineral metabolism, the therapeutic effects of Achyranthes bidentata on steroid-induced ONFH remain unclear. Thus, the aim of the current study was to verify whether Achyranthes bidentata extract (ABE) can be used to prevent steroid-induced ONFH and to investigate its underlying pharmacological mechanisms. Methods Steroid-induced ONFH rat models were established to evaluate the effects of ABE treatment on osteonecrotic changes and repair processes. Microfocal computed tomography (Micro-CT) was performed to assess the effects of ABE treatment on bone mass, microstructure, and vascularization. Then, the effects of ABE treatment on osteoclast differentiation and bone formation were also evaluated in vivo and in vitro. In addition, receptor activator of nuclear factor kappa B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) expression in sera, femoral heads and bone marrow-derived mesenchymal stem cells (BMSCs) were detected at both protein and mRNA levels. Results The ratio of empty lacuna, adipose tissue area, and adipocyte perimeter in the bone marrow were markedly lower in the ABE treatment groups than in the model group. Micro-CT evaluation indicated that ABE treatment could improve the microstructure of the trabecular bone, increase bone mineral density and promote vascularization in steroid-induced ONFH rats. Moreover, ABE treatment inhibited osteoclast differentiation and activated bone formation markers. Interestingly, OPG downregulation, RANK and RANKL upregulation, and an increased ratio of RANKL to OPG in sera and necrotic femoral head could be reversed by ABE treatment, which also effectively inhibited RANKL-induced osteoclast differentiation and regulated RANKL and OPG expression of in vitro. Conclusion ABE may prevent steroid-induced ONFH and alleviate steroid-induced bone deterioration by regulating the RANKL/RANK/OPG signaling pathway.

The ability to adroitly tailor acid-strength using specifically-engineered bimetallic nanoporous materials has been investigated with a view to exploiting their potential in solid-acid catalysed transformations. Further, it has been demonstrated that through site-specific interactions, extra-framework zinc ions can suitably modify the acidity of Brønsted acid sites, to stimulate diverse catalytic responses, when combined with isomorphously-substituted framework metal cations within porous architectures, for the Beckmann rearrangement of cyclohexanone oxime and in the isopropylation of benzene.

The organised nanostructure of mesoporous platinum deposited from the H(I) phase of a lyotropic liquid crystal template contains a regular, hexagonal array of uniform nanometre diameter cylindrical pores. This structure is ideally suited to the investigation of the interfacial capacitance and properties of ionic liquids confined within small pores of the type found in the high surface area electrodes favoured for supercapacitors and batteries. Cyclic voltammetry experiments for BMIM-PF(6) show a large capacitance for the mesoporous Pt electrode, confirming that the ionic liquid fills the 2 nm pores. The value of the specific capacitance, normalised to the total surface area, for the ionic liquid within the pores is approximately twice as large as the corresponding value at a flat Pt surface. Impedance measurements, using a small amplitude perturbation, give a value for the capacitance about one order of magnitude less than that from cyclic voltammetry where the amplitude of the perturbation is much larger. The impedance measurements show that the conductivity of the ionic liquid within the pores is at least three orders of magnitude lower than that in the bulk indicating highly restricted mobility for the ions in these narrow pores. The implications of these results for applications in supercapacitors and batteries are discussed.

O-linked N-acetylglucosamine glycosylations (O-GlcNAc) and O-linked phosphorylations (O-phosphate), as two important types of post-translational modifications, often occur on the same protein and bear a reciprocal relationship. In addition to the well documented phosphorylations that control Akt activity, Akt also undergoes O-GlcNAcylation, but the interplay between these two modifications and the biological significance remain unclear, largely due to the technique challenges. Here, we applied a two-step analytic approach composed of the O-GlcNAc immunoenrichment and subsequent O-phosphate immunodetection. Such an easy method enabled us to visualize endogenous glycosylated and phosphorylated Akt subpopulations in parallel and observed the inhibitory effect of Akt O-GlcNAcylations on its phosphorylation. Further studies utilizing mass spectrometry and mutagenesis approaches showed that O-GlcNAcylations at Thr 305 and Thr 312 inhibited Akt phosphorylation at Thr 308 via disrupting the interaction between Akt and PDK1. The impaired Akt activation in turn resulted in the compromised biological functions of Akt, as evidenced by suppressed cell proliferation and migration capabilities. Together, this study revealed an extensive crosstalk between O-GlcNAcylations and phosphorylations of Akt and demonstrated O-GlcNAcylation as a new regulatory modification for Akt signaling.

Background Processed Chuanwu (PCW), the mother root of Aconitum carmichaeliiDebeauxv, has been widely used as a classic Traditional Chinese Medicine for pain relieve for over two millennia clinically. However, its action on chronic inflammatory pain has not been clarified. Here, we investigated the antinociceptive effect of PCW in complete freund’s adjuvant (CFA)-induced mice and its possible mechanisms associated with opioid system and TRPV1 ion channel. Methods Male ICR mice were intraplantarly injected with CFA. PCW (0.34, 0.68 and 1.35 g/kg) was orally given to mice once a day for 7 days. Von frey hairs and planter test were assessed to evaluate the antinociceptive effect of PCW. To investigate the participation of dynorphin/opioid system in PCW antinociception, subtype-specific opioid receptor antagonists or anti-dynorphin A antiserum were used. To eliminate other central mechanisms that contribute to PCW antinociception, hot plate (50 °C) test were performed. Further, involvements of TRPV1 in PCW antinociception were evaluated in CFA-induced TRPV1−/− and TRPV1+/+ C57BL/6 male mice, and in capsaicin-induced nociception ICR naive mice pretreated with nor-BNI. Meanwhile, calcium imaging was performed in HEK293T-TRPV1 cells. Finally, rotarod, open-field tests and body temperature measurement were carried out to assess side effects of PCW. Results PCW dose-dependently attenuated mechanical and heat hypersensitivities with no tolerance, which could be partially attenuated by coadministration of k-opioid receptor antagonist nor-binaltorphimine (nor-BNI) or anti-dynorphin A (1–13) antiserum. And PCW antinociception was totally erased by pretreatment with nor-BNI in the hot plate test. In addition, PCW antinociception was decreased in TRPV1−/− mice compared to TRPV1+/+ group. And PCW still manifested inhibitory effects in capsaicin-induced nociception with nor-BNI pretreatment. PCW significantly inhibited capsaicin-induced calcium influx in HEK293T-TRPV1 cells. Finally, no detectable side effects were found in naive mice treated with PCW. Conclusions This study shows PCW’s potent antinociceptive effect in inflammatory conditions without obvious side effects. This effect may result from the activation of κ-opioid receptor via dynorpin release and the inhibition of TRPV1. These findings indicate that PCW might be a potential agent for the management of chronic inflammatory pain.